2010年6月23日，北京生命科學(xué)研究所襲榮文實(shí)驗(yàn)室在Development雜志上在線發(fā)表文章揭示結(jié)節(jié)性硬化癥致病基因?qū)S系果蠅生殖干細(xì)胞的重要作用,。
結(jié)節(jié)性硬化癥致病基因產(chǎn)物TSC1和TSC2具有在進(jìn)化上高度保守的通過(guò)抑制TOR來(lái)控制細(xì)胞生長(zhǎng)的功能,。在這篇論文中，研究人員發(fā)現(xiàn)TSC1/2對(duì)維系果蠅生殖干細(xì)胞也起非常重要的作用,。失去這些基因功能的生殖干細(xì)胞過(guò)早發(fā)生了分化,，不能進(jìn)行自我更新，從而導(dǎo)致干細(xì)胞的丟失,。這種干細(xì)胞丟失現(xiàn)象可以被藥物雷帕霉素(rapamycin)處理或S6k突變所抑制,，說(shuō)明干細(xì)胞丟失是由于TORC1的過(guò)過(guò)度激活導(dǎo)致的。在機(jī)制上,，TORC1的過(guò)度激活可以抑制BMP信號(hào)通路在干細(xì)胞內(nèi)的活性,，而B(niǎo)MP信號(hào)是維系干細(xì)胞自我更新的主要因子。另外,，TORC1的過(guò)度激活也可以激活一個(gè)不依賴BMP-BAM通路的分化途徑,，最終導(dǎo)致生殖干細(xì)胞的分化。
本論文揭示了結(jié)節(jié)性硬化癥致病基因產(chǎn)物在干細(xì)胞調(diào)節(jié)中的一個(gè)新的,，在進(jìn)化上有可能保守的功能,。這一新機(jī)制的發(fā)現(xiàn)有助于進(jìn)一步理解干細(xì)胞在體內(nèi)的自我更新與分化調(diào)節(jié)的平衡機(jī)制，并對(duì)理解結(jié)節(jié)性硬化癥的病理及尋找防治措施具有參考作用,。
北京生命科學(xué)研究所與協(xié)和聯(lián)合招生研究生孫培為該論文的第一作者,。其他作者還有研究生權(quán)爭(zhēng)輝，畢設(shè)生張博迪和伍拓琦,。襲榮文博士為論文通訊作者,。此項(xiàng)研究為科技部和北京市科委資助課題，在北京生命科學(xué)研究所完成,。(生物谷www.Bioon.net)
生物谷推薦原文出處：
Development doi: 10.1242/dev.051466
TSC1/2 tumour suppressor complex maintains Drosophila germline stem cells by preventing differentiation
Pei Sun, Zhenghui Quan, Bodi Zhang, Tuoqi Wu and Rongwen Xi*
Tuberous sclerosis complex human disease gene products TSC1 and TSC2 form a functional complex that negatively regulates target of rapamycin (TOR), an evolutionarily conserved kinase that plays a central role in cell growth and metabolism. Here, we describe a novel role of TSC1/2 in controlling stem cell maintenance. We show that in the Drosophila ovary, disruption of either the Tsc1 or Tsc2 gene in germline stem cells (GSCs) leads to precocious GSC differentiation and loss. The GSC loss can be rescued by treatment with TORC1 inhibitor rapamycin, or by eliminating S6K, a TORC1 downstream effecter, suggesting that precocious differentiation of Tsc1/2 mutant GSC is due to hyperactivation of TORC1. One well-studied mechanism for GSC maintenance is that BMP signals from the niche directly repress the expression of a differentiation-promoting gene bag of marbles (bam) in GSCs. In Tsc1/2 mutant GSCs, BMP signalling activity is downregulated, but bam expression is still repressed. Moreover, Tsc1 bam double mutant GSCs could differentiate into early cystocytes, suggesting that TSC1/2 controls GSC differentiation via both BMP-Bam-dependent and -independent pathways. Taken together, these results suggest that TSC prevents precocious GSC differentiation by inhibiting TORC1 activity and subsequently differentiation-promoting programs. As TSC1/2-TORC1 signalling is highly conserved from Drosophila to mammals, it could have a similar role in controlling stem cell behaviour in mammals, including humans.
